Parkinson's Disease (PD) is a crippling motor and cognitive disorder affecting 1 in 100 people in developed countries. Current therapies cause numerous undesirable side effects and are not effective in the long-term. The death of dopamine neurons in the midbrain is known to be a major contributor to the disease phenotype; however, the underlying changes in brain circuitry that result from chronic loss of dopamine remain elusive. Understanding these changes is crucial for the development of improved drugs and therapies. Our fundamental goal is to understand the causal mechanisms of Parkinsonian symptoms within the brain in order to more accurately target therapies. The two major circuits which comprise the basal ganglia, a set of nuclei in the forebrain that receive significant dopaminergic input, are differentially affected by dopamine loss. The direct pathway, which promotes movement, becomes hypoactive whereas the indirect pathway, which inhibits movement, becomes hyperactive. Changes in intrinsic properties of striatal medium spiny neurons (MSNs), the output neurons of the striatum, have been a major focus of PD research, whereas changes in synaptic inputs that drive these neurons have received little attention. Until recently, investigation of Parkinsonian neuropathology was limited to anatomical studies that provide only static snapshots of a complex and dynamic disorder. With the advent of optogenetics - light-activated ion channels that can be targeted to genetically defined neuronal populations - dissecting the basic circuitry involved in the disease has become feasible. In this proposal we will employ innovative techniques to measure how inputs that drive the basal ganglia change after dopamine depletion, and to investigate whether altering the activity of specific inputs in behaving animals can ameliorate Parkinsonian symptoms. With our findings we hope to shed light on the brain bases of the Parkinsonian phenotype, thus revealing targets for intervention in human patients. PUBLIC HEALTH RELEVANCE: Parkinson's disease treatments have advanced very little in recent decades, and the lack of current knowledge of how the disease affects the brain is a major stumbling block. Heavy focus has been aimed at understanding changes within a particular structure known as the basal ganglia, while the inputs that drive this system have received less attention despite their hypothesized role in causing disease symptoms. This proposal employs cutting edge techniques to conclusively reveal changes in the forces that drive this brain system into a Parkinsonian state in the hopes of finding specific sites for targeted therapeutic intervention.